Actemra May Have Lipid Benefits

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In this study, patients with rheumatoid arthritis treated with the interleukin (IL)-6 receptor blocker tocilizumab (Actemra) experienced the expected increases in lipids, but also had favorable alterations in certain types of lipid particles and other biomarkers that have been linked with vascular disease.

Note that the overall clinical impact of such cardiovascular changes in patients with rheumatoid arthritis treated with tocilizumab is unknown.

Patients with rheumatoid arthritis treated with the interleukin (IL)-6 receptor blocker tocilizumab (Actemra) experienced the expected increases in lipids, but also had favorable alterations in certain types of lipid particles and other biomarkers that have been linked with vascular disease, researchers found.

After 3 months of treatment, patients receiving tocilizumab had a 12.6% increase in median total cholesterol, whereas those receiving placebo had an increase of 1.7% (P<0.01), according to Iain B. McInnes, MD, PhD, of the University of Glasgow, and colleagues.

Patients with rheumatoid arthritis are at increased risk for cardiovascular disease that can't be fully explained by traditional risk factors, and it has become increasingly clear that the underlying inflammatory state may contribute to this.

Treatment with tocilizumab has been associated with lipid elevations, but little is known about the effects of tocilizumab treatment on lipid subparticles and on other markers such as clotting factors.

In addition, IL-6 itself has been implicated in the development of coronary heart disease, and some previous research has suggested that blocking this signaling pathway might be protective. Accordingly, the researchers conducted a multicenter phase III trial known as MEASURE that examined multiple aspects of vascular risk in patients with active rheumatoid arthritis.

A total of 132 patients were included. The primary study objective was to assess the effects of tocilizumab on pulse wave velocity and small LDL particle number, with the hypothesis that IL-6 blockade would decrease both.

By week 12, LDL cholesterol increased by 28.1% with tocilizumab treatment, compared with 2.2% with placebo. Triglycerides rose by 10.6% with the active treatment and fell by 1.9% with placebo (P<0.01 for both).

Contrary to expectations, no differences were seen in the number of small LDL particles, with an adjusted mean difference of -0.0 nmol/L (95% CI -115-115) at week 12 and 11.2 nmol/L (95% CI -106.7 to 129.1) at week 24.

There also were no differences in total HDL or oxidized LDL cholesterol.

The change in pulse wave velocity was greater in the placebo group at week 12, with an adjusted mean difference of 0.79 m/s (95% CI 0.22-1.35, P=0.0067), but significance was lost at 24 weeks.

Pulse wave velocity "is a measure of early structural vascular changes and has been shown to respond within 3 months to changes in vascular inflammation," the researchers explained.

Potential reasons for the unexpected finding that treatment had no effect on this parameter was that there were technical difficulties in performing the procedure for patients with severe disease, and that patients may already have had vascular disease progression that was less amenable to treatment effects.

Total serum HDL cholesterol levels didn't change during the course of treatment. However, nuclear magnetic resonance revealed differences according to particle sizes, with increases of 23% from baseline in median concentration of small HDL and decreases of 25% in medium HDL particles. The corresponding figures for placebo were 2.8% and 2%, respectively.

The increase in small HDL particles -- which typically are lower in patients with rheumatoid arthritis -- suggested that treatment with tocilizumab may "normalize" the level of these subparticles, according to the researchers.

Paraoxonase 1 also was increased by 16% in the tocilizumab group, while secretory phospholipase A2-IIA declined by 61%.

"The observed reduction in medium HDL and HDL-[serum amyloid A] concentrations, along with the increase in paraoxonase, an antioxidant enzyme associated with HDL, suggests remodeling of HDL particles from a pro-inflammatory to an anti-inflammatory phenotype in response to tocilizumab treatment," McInnes and colleagues explained.

They also found that inflammatory markers such as C-reactive protein, which were high at baseline, declined with treatment, as did the thrombogenic factors fibrinogen and D-dimer.

Further exploration of that "net vascular effect" in patients with rheumatoid arthritis and others "is of major interest, particularly given the recent data from large-scale (>130,000 subjects, >25,000 coronary heart disease cases) genome-wide association studies that suggest a potentially detrimental effect of IL-6R signaling on the risk for coronary heart disease," they concluded.

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